pH-sensitive TALK1 channel in islet-ductal interactions

Insulin is produced and secreted by pancreatic beta cells and functions as a key anabolic hormone. The general role of this hormone is to allow nutrients to enter cells and support cell housekeeping, energy metabolism, and storage. The lack of insulin or its action in an organism prevents these processes, leads to diabetes mellitus and if not managed, progressively to deterioration of cells, organ failure, and death. During the last decades, a prevailing view in the field has been that beta cells respond to increased plasma nutrient levels and subsequent increase in cytosolic ATP availability with a sequence of events from closure of ATP-dependent potassium channels, cell membrane depolarization, and opening of voltage-activated calcium channels, increased cytosolic calcium, followed by a calcium-dependent exocytosis of insulin. It is becoming increasingly clear that the repertoire of ion channels expressed in beta cells is much broader and diverse than originally though. The function of these other ion channels is mostly unknown, but could play an important role in fine- tuning the response of beta cells either to metabolic challenges of the whole organism or to changes in the local cellular environment. In recent genome-wide association studies, a novel pH-sensitive 2- pore domain potassium channel TALK1, which is exclusively expressed in the pancreas, has been found to exhibits strong positive correlation with the development of type 2 diabetes mellitus. The gating of this ion channel is regulated by the extracellular pH changes and could therefore represent a link between pancreatic ductal cell activity and beta cell membrane excitability, beta cell network activity, and insulin release, in particular after secretin-stimulated activity of the former postprandially. The proposed collaborative study is the first attempt to address the aforementioned functional link on a cell population level and presents unique entanglement of molecular, and novel cellular and complex network theory approaches between the partner laboratories.

Insulin secreting beta cells in pancreas regulate their activity with ion channels in the plasma membrane. pH sensitive ion channel TALK1 is a most abundant channel protein in beta cells and is closed in acidic and open in alkaline cellular environment, suggesting it can play an important role in normal beta cell function and disfunction. Our results confirm the sensitivity of beta cell collectives to changes in extracellular pH, possibly also due to islet-ductal interactions.